Ketogenic Diet for Treatment Resistant Depression Shows Modest Short Term Benefit
A randomized clinical trial suggests small early improvements in severe depression, with uncertain durability and clinical impact.
In adults with treatment-resistant depression, a ketogenic diet added to usual antidepressant therapy led to a modest improvement in depression scores at 6 weeks, but the benefit was not sustained at 12 weeks and required intensive dietary support.
Study Details
A randomized clinical trial published in JAMA Psychiatry evaluated whether a ketogenic diet could improve outcomes in adults with treatment-resistant depression.
The study was led by Min Gao, PhD, and colleagues at the University of Oxford. Treatment-resistant depression was defined as persistent depressive symptoms despite ongoing antidepressant therapy, with participants scoring 15 or higher on the 9-item Patient Health Questionnaire (PHQ-9).
The ketogenic diet, long used in epilepsy management, has increasingly been explored for psychiatric conditions such as bipolar disorder and schizophrenia. The biological rationale centers on ketone metabolism, mitochondrial function, inflammation, and neurotransmitter modulation.
Methodology
The trial was conducted in the U.K. from February to June 2024.
88 adults aged 18 to 65 with treatment-resistant depression were randomized.
44 participants received a ketogenic diet.
44 participants received a phytochemical control diet emphasizing fruits, vegetables, and unsaturated fats.
Both groups received weekly individualized dietetic support.
The ketogenic group consumed fewer than 30 grams of carbohydrates per day, with 15% to 20% of calories from protein. Prepared meals were delivered to support adherence.
The primary endpoint was change in depression severity at 6 weeks measured by PHQ-9. A key secondary endpoint assessed outcomes at 12 weeks.
Key Findings
At 6 weeks, PHQ-9 scores decreased by 10.5 points in the ketogenic group versus 8.3 points in the control group (P = 0.05).
The between-group difference was approximately 2 points on a 27-point scale.
Remission at 6 weeks occurred in 25% of the ketogenic group versus 9% in the control group.
By 12 weeks, the difference between groups was no longer statistically significant.
No meaningful differences were observed in anxiety, anhedonia, cognition, quality of life, or functional outcomes.
Urinary ketone levels were not significantly associated with PHQ-9 improvement.
No serious adverse events were reported, though long-term safety was not assessed.
Importantly, the effect size did not meet the commonly accepted 5-point threshold considered clinically significant for PHQ-9 improvement.
Adherence required intensive weekly dietitian support, and few participants continued the ketogenic diet after structured support ended.
Implications for Practice
For patients with treatment-resistant depression, this trial suggests that a ketogenic diet may provide a modest short-term reduction in depressive symptoms when added to standard pharmacotherapy. However, the magnitude of improvement was small and not sustained at 12 weeks.
From a patient perspective, the diet is demanding. Carbohydrate restriction below 30 grams per day requires substantial lifestyle changes and structured support. It is not a replacement for antidepressant therapy and should not delay evidence-based psychiatric care.
For clinicians, this study provides early randomized evidence supporting metabolic interventions in depression, but it also highlights key limitations. The short intervention period, modest effect size, lack of sustained benefit, and reliance on intensive support limit immediate integration into routine practice. The trial does open the door to further investigation of metabolic psychiatry, including whether specific subgroups, such as those with more severe depression or metabolic dysfunction, may derive greater benefit.
At present, ketogenic diets may be considered investigational adjunctive strategies rather than standard-of-care treatment for treatment-resistant depression.